Attention Deficit Hyperactivity Disorder (ADHD) is a serious public health problem that affects between 3 to 9% of children and accounts for between 30 to 40% of child referrals to mental health services. While the pathogenesis of this illness remains poorly understood, ADHD is increasingly seen as a neurodevelopmental disorder implicating inhibitory regulation, executive function, motivational processes, perception and motor control. Our long-term goal is to increase our understanding of neurodevelopmental deviations in pediatric ADHD. The objective of this renewal application is to test whether alterations of the earlier developing striatum precede alterations that occur later in the slower developing prefrontal areas such as the dorsolateral prefrontal cortex (DLPFC). From childhood to adolescence, the brain undergoes substantive structural and functional changes with differential timing, which parallel the maturation of cognition and behavior. This process of fine-tuning or maturing cognitive performance includes the elimination of overproduced neuronal connections or synapses, which can be assessed using the noninvasive neuroimaging method, in vivo phosphorous (31P) spectroscopy. From our first-cycle of funding, the cross-sectional in vivo 31P spectroscopy results acquired at 1.5 Tesla show basal ganglia deficits suggesting an underdevelopment of dendritic branching and synaptic formations, and prefrontal cortex deficits but only in the relatively older ADHD children suggesting an underachieved maturational process of fine-tuning. However, to definitively assess developmental changes over time requires longitudinal measurements. Therefore, the aims of this study are to acquire longitudinal whole-brain 3D multi- voxel 31P spectroscopy and ultra-high resolution anatomical MRI measurements at 4 Tesla in children and adolescent with and without ADHD; that is baseline plus two follow-up visits 12-months apart. Using a high- field MR system dramatically improves the regional specificity and biochemical resolution. Deviations in cortical surface topography will be assessed as well as neuropsychological measures targeting different cognitive/behavioral domains will be collected at each time point. The overall hypothesis of this longitudinal study is that children with ADHD will demonstrate regional deviations in neurodevelopmental trajectories relative to healthy controls including in the slower developing DLPFC, but not until the onset of the fine-tuning processes in the DLPFC that occurs late in childhood. Significance: If confirmed, these studies will provide more direct evidence of a developmental mechanism targeting a bottom-up dysfunction in the striatum potentially impairing the fine-tuning of control processes or executive functions in the prefrontal cortex of children with ADHD. Additionally, these observations will establish a foundation of biochemical trajectories in pediatric ADHD contrasted against healthy controls, which may lead toward improved assessment and treatment of ADHD. PUBLIC HEALTH RELEVANCE Attention Deficit Hyperactivity Disorder (ADHD) is a serious public health problem that affects between 3 to 9% of children and accounts for between 30 to 40% of child referrals to mental health services. While the cause of this illness remains poorly understood, ADHD is increasingly seen as a neurodevelopmental disorder. This work promises to identify where in the brain and at what age certain alterations occur in children and adolescents with ADHD, and this information of changes with age can then potentially be used as a predictor of treatment outcome. .